SLC25A15 encodes a mitochondrial ornithine-citrulline antiporter that plays a critical role in the urea cycle by facilitating electroneutral exchange of cytosolic ornithine for mitochondrial citrulline plus a proton 12. The transporter also mediates transport of lysine and arginine through antiport mechanisms 1. By connecting cytosolic and intramitochondrial urea cycle reactions, SLC25A15 is essential for ammonia detoxification and nitrogen metabolism. Loss-of-function mutations in SLC25A15 cause hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a rare autosomal recessive urea cycle disorder characterized by impaired mitochondrial ornithine transport, hyperammonemia, and homocitrulline excretion 34. Patients present with variable phenotypes including developmental delay, seizures, ataxia, and hepatic dysfunction 3. Early dietary management with protein restriction and ammonia scavengers can improve outcomes 3. Beyond monogenic disease, SLC25A15 functions as a tumor suppressor in hepatocellular carcinoma (HCC). Hypoxia-induced SLC25A15 downregulation promotes HCC progression through reprogramming of glutamine metabolism via SLC1A5 regulation, and SLC25A15-deficient HCC cells show increased sensitivity to glutaminase inhibitors and anti-PD-L1 therapy 5. Additionally, SLC25A15 upregulation drives liver metastasis formation in ESR1-mutated breast cancer through urea cycle dysregulation 6. Rare disease experts recommend SLC25A15 screening in newborn genome sequencing programs 7.